3-aminoethers of 3beta-hydroxy androstanes



United States Patent ()flice 3,210,386 S-AMINOETHERS F Sfl-HYDROXYANDROSTANES Robert D. Birkenmeyer, Fred Kagan, Daniel Lednicer,

and Barney J. Magerlein, Kalamazoo, Mich., assignors to The UpjohnCompany, Kalamazoo, Mich., a corporation of Delaware N0 Drawing. FiledJan. 9, 1961, Ser. No. 81,270 7 Claims. (CL 260-397.3)

This invention relates to new steroid compounds and is particularlyconcerned With 3-aminoethers and 3- aminothioethers of 3fi-hydroxysteroids of the androstane series having the formulae:

3)u V- R and X i R N ''(CH2)D''V" R I wherein n has a value of 2 to 6,inclusive, wherein is selected from the group consisting of B CK and

011 -05, onvom wherein V is selected from the group consisting of theelements oxygen and sulfur; and wherein Y is selected from the groupconsisting of methyl and hydrogen.

Furthermore, in the above formulae when V is oxygen W is selected fromthe group consisting of O=CIJ l l and When V is, however, sulfur then Wis selected from the group consisting of Patented Oct. 5, 1965 H I \C Iand In the above formulae the parameter X is selected from the groupconsisting of HO AcO HO O=(|3; l 1 I and providing W is and V is oxygen.

Paramater X signifies also HO AcO HO O==(|1; l l l I and it HCEC/ when Vis sulfur and W is When W is and V is oxygen, however, then X isselected from the group consisting of HO A00 no a p' a H, l H, l H8O andThe term Ac in the above parameters refers to the acyl radical of ahydrocarbon carboxylic acid containing from one to eight carbon atoms,inclusive.

Furthermore; the invention relates to the N-oxides of the above definedproducts and the acid mineral salts of the above defined products,particularly the hydrochlorides and sulfates.

Additionally, the invention is concerned with the process of productionfor the above compounds.

The process of production of the compound of the structure shown aboveessentially comprises: conversion of a selectedB-hydroxy-17-keto-andro-stane or 3-hydroxy- 17-keto-androstene to the3-aminoether thereof with a selected amino-alkyl chloride by generallyknown procedures. Depending on the procedure chosen, it may be necessaryto protect the 17-keto group of the starting compound of the androstaneseries, for example, by ketalization. In the event that it is desired tohave a 11- keto steroid other as a final product, it will often benecessary to use a starting 3-hydroxy-17-keto steroid with an ll-oxygroup and to oxidize this material to the corresponding ll-keto productafter the ether linkage has been established.

To obtain 3-thioether, the same processes are carried out with acompound selected from the 3-meroaptoandrostane series.

The amino ether, obtained in the form of a salt, can be converted to thefree basic amino ether by treatment with a base, and can be, if desired,converted to the salts of other acids by treating the free amino etherbase with site? acids. Additional reactions after etherification inc ue:

( 1) Catalytic hydrogenation to convert A -androstene 3-ethers to thecorresponding saturated androstane 3-ether.

(2) Conversion of 17 8-hydroxyl group to a 17fl-acy1oxy group byesterification.

(3) Conversion of the l7-keto group with a Grignard to the17fi-hydroxy-17a-alkyl or ethynyl group.

(4) Conversion of the free tertiary amino steroid ether to its N-oxide.

The compounds produced by these reactions have hypocholesteremicactivity. The compounds are thus useful in the treatment ofatherosclerosis which is a form of arteriosclerosis which ischaracterized by the fatty degeneration occurring in the arterial walls,by mechanisms not yet definitely established. Hypercholesteremia refersessentially to an excess of cholesterol in the blood serum. While thecauses of hypercholesteremia and the nature of its role inatherosclerosis and related conditions is not clearly understood,considerable effort has been directed toward reducing blood and tissuecholesterol levels as an attack upon the clinical conditions in whichhigh levels are implicated. It has long been recognized that certainsubstances such as sitosterol, corn oil, and nicotinic acid are capableof reducing in small degree the blood and tissue cholesterol contents,either by interfering with the absorption of exogenous cholesterolintroduced with food, or by facilitating the excretion of cholesterolfrom the body. Major emphasis, however, has been placed on the searchfor compounds which will interfere with the production of endogenouscholesterol by the liver and hence offer a more positive means ofcontrol of cholesterol levels.

The novel compounds of the present application significantly reduce thecholesterol content of both blood and tissue by partially arresting thebiosynthesis of cholesterol in the body.

The new compounds, especially in their hydrochloric acid salt form, arealso active against parasite-produced diseases in animals. They areparticularly active against species of Trypanosoma, such as Trypanosamaequiperdum and Trichomonas such as T richo mvnas vagirzalis, Entamoebahisto lytica, Entamoeba coli and against many of the eggs and larvae ofcommon animal parasites. The novel materials, therefore, can be usedagainst Trichomonas vaginalis, incorporated into suppositories orbougies or, can be used in sprays and as powders, in animal bedding, forcattle or poultry in order to prevent parasitic diseases.

Starting materials for this application, are materials such asdehydroepiandrosterone, dehydroepiandrosterone mercaptan [Bernstein, J.Org. Chem. 16, 679 (1951)], 3fi-hydroxy-6-methyl-17-keto-5-androstene[Greenville et al., J. Chem. Soc. (London), 4105 (1957)] and 11;?-hydroxy derivatives of the before-mentioned compounds prepared bymethods shown in the preparations.

In carrying out the process of the present invention, the selectedstarting materials, 3-hydroxy-17-keto steroids, are dissolved in anorganic solvent, and reacted with the selected di-N-substitutedaminoalkyl chloride. The reaction is carried out in the presence of analkali metal metathetically reactive reagent, such as triphenylmethylsodium or triphenylmethyl potassium, metal hydrides such as sodium orpotassium hydride or an alkyl alkali metal compound such as propyl orbutyl lithium or propyl or butyl sodium, providing that in this eventthe 17-keto group must be protected by a keto-protecting group such asketalor semic-arbazone formation.

The amount of the di-N-substituted amino alkyl chloride used in thisreaction is preferably in excess of one mole (5-50%) per mole ofsteroid. The base alkali metal metathetically acting reagent is used ina ratio of 1.1 moles of base per mole of steroid. These quantities,however, are not critical and larger amounts can be used.

The ketal derivative which is used in the preferred embodiment of thisreaction is usually produced by react ing the 17-keto steroid withglycols, wherein the total number of carbon atoms is up to 8, inclusive,and wherein the hydroxyl groups are on carbon atoms separated at themost by one methylene group.

The reaction mixture for the etherification is usually kept at refluxtemperature, that is depending on the solvent between 60 and 120 C., andthe period of reflux is usually about 2 to 24 hours. After the reactionis terminated, the product is recovered by conventional methods, that isby extraction, recrystallization or chromatography with organicsolvents. Since the tertiary amino compound is easily converted to itshydrochloride, in which form it is water-soluble, it is usuallyextracted from the reaction mixture with aqueous hydrochloric acid.Ether can be added to the reaction mixture for better results in theextraction. Since the free amino base is found to be usually a viscousoil rather than crystalline material, the product is generally used inthe form of its hydrochloric acid or sulfuric acid salts. Furtherchemical conversions of the thus-obtained amino-ethers are disclosed inthe examples.

PREPARATION 1 3,6- (Zdiethylaminoethoxy -5-andr0sten-1 7 -one A 5percent molar excess of sodium triphenylmethyl was added to a solutionof 10 grams of dehydroepiandrosterone, dissolved in milliliters ofbenzene. A solution of 5.2 grams of diethylaminoethyl chloride,dissolved in 10.5 milliliters of toluene, was added to the reactionmixture which was then stirred at about 25 for one hour and heated atreflux temperature for two hours. The reaction mixture was filtered, theprecipitate collected and suspended in about 200 milliliters oftetrahydrofuran. Five grams of diethylaminoethyl chloride, dissolved in10 milliliters of toluene, was added and this mixture heated at refluxtemperature for three hours. The reaction mixture was concentrated undervacuum and the residue dissolved in a mixture of benzene and water. Theorganic layer was washed three times with water, dried and concentratedunder vacuum. The residue was dissolved in ether and gaseoushydrochloric acid bubbled into the solution. The precipitate whichformed was collected, dried, dissolved in water, made alkaline and steamdistilled. The residue was extracted with, ether,

dried and concentrated. The residual material was dissolved in ether andthe ether solution extracted twice with dilute hydrochloric acid. Thecombined aqueous phases were neutralized with sodium hydroxide andextracted with methylene dichloride. The methylene dichloride extractswere concentrated under vacuum to yield 3.5 grams of a dark oil. Onegram of this crude material was dissolved in methylene dichloride,placed on 100 grams of Florisil anhydrous magnesium silicate and elutedgradiently [Skellysolve B hexanes 100 percent to Skellysolve B hexanes80 percent and 20 percent acetone at fraction 17, inclusive] collecting200 milliliter fractions. Fractions 9 through 17, inclusive, werecombined, dissolved in ether and ethereal hydrochloric acid added. Theresulting precipitate was collected and recrystallized once from ethylacetate and once from methanol-ether to a melting point of 194197 and arotation of plus 17 in methanol.

Analysis-Calcd. for C H ClNO C, 70.80; H, 9.98; N, 3.30. Found: C,70.63; H, 10.21; N, 3.49

PREPARATION 2 3 ,8- (Z-diethylaminoethoxy -5 -andrsten-1 7 one A mixtureof 100 grams of dehydroepiandrosterone, 100 milliliters of ethyleneglycol, 1500 milliliters of henzene and 2 grams of para-toluenesulfonicacid were heated under reflux for a period of five hours while removingwater from the condensate with a trap. The reaction mixture wasthereupon cooled to 30 degrees, washed with 200 milliliters of percentpotassium bicarbonate solution, dried over sodium sulfate and finally200 milliliters of benzene was distilled to complete the drying process.To the residue there was added 0.37 mole of butyl lithium, dissolved inhexane, followed by 0.38 mole of diethylaminoethyl chloride, dissolvedin toluene. The reaction mixture was heated under reflux for 23 hours.The mixture was then cooled, diluted with 1 liter of ether and extractedwith three successive 800 milliliter portions of dilute hydrochloricacid (80 milliliters of concentrated hydrochloric acid diluted withwater to :800 milliliters). The aqueous extract was washed with 800milliliters of ether. The combined organic extracts were dried andevaporated to yield 35 grams of recovered dehydroepiandrosterone.

The aqueous solution was extracted with 800 milliliter, 400 milliliter,and again 400 milliliter portions of methylene dichloride. Thesecombined extracts were dried and concentrated. The residue was dissolvedin a minimum of methylene dichloride and added to 2 liters of ether. Theprecipitate was collected by filtration, washed with ether and dried. 79grams (53.8 percent yield) of3,8(2-diethylaminoethoxy)-5-androsten-17-one was obtained.

PREPARATION 3 3B-hydr0xy-6 methyl-5 -andr0sten-1 7-0ne To a solution of3.5 grams of 3B-hydroxy-6-methyl-5- androsten-17-one 3-acetate [J. Chem.Soc.(London) 4105 (1957)] in 30 milliliters of ethanol was added asolution of 80 milligrams of potassium hydroxide in two milliliters ofwater. The mixture was allowed to stand for a period of four hours underoccasional shaking and was then poured into 150 milliliters of water.The solution was neutralized with dilute hydrochloric acid and theprecipitate which was thus obtained was removed by filtration and washedwith water. The material was twice recrystallized from methanol to getpure 3fi-hydroxy-6- methyl-S-androsten-17-one.

PREPARATION 4 313-mercapt0 6-methyZ-S-androsten-Z 7 -one A mixture of 2grams of 3B-hydroxy-6-methyl-5- androsten-17-one, 5 milliliters ofpyridine and 5 milliliters of paratoluenesulfonyl chloride was allowedto stand at room temperature for a period of four hours. Thereafter 6the mixture was poured into 100 milliliters of water and this mixturewas allowed to stand overnight in a refrigerator. The mixture was thenfiltered and the product recrystallized from methanol two times to give318-ptoluenesulfonate of 3fi-hydroxy-6-methyl-S-androsten-17- one.

1.5 grams of 3fl-hydroxy-6-methyl-5-androsten-17-one3-p-toluenesulfonate, 3 grams of thiourea, 1.8 milliliters of pyridineand 18 milliliters of ethanol were refluxed on a steam bath for fourhours. The mixture was diluted with water and left in a refrigerator for20 hours at a temperature of about 5 degrees centigrade. The thusprecipitated crystals were collected, washed with 25 percent alcohol andpercent water solution and thereupon recrystallized three times frommethanol and acetone to give 3-isothiuronium p-toluenesulfonate of 35-hydroxy-6-methyl-5-androsten-17-one of formula:

CH3 a I NHg 314-- u 600 milligrams of the 3-(isothiuroniumpara-toluenesulfonate) of 3B-hydroxy-G-methyl-S-androsten 17 one wasrefluxed with a solution of 0.15 gram of sodium hydroxide in 15milliliters of ethanol. To this mixture 1.2 milliliters of water wereadded and the mixture was refluxed for additionally 2 hours on awater-bath and thereafter poured into ice water. The mixture wasacidified with glacial acetic acid whereupon a finally dividedprecipitate separated. The precipitate was collected, washed with waterand recrystallized from benzene petroleum ether mixture to give pure3fi-mercapto-6-methyl- 5-androsten-17-one.

PREPARATION 5 3,8,1 1 B-dihydroxy-S -androsten:-1 7 -one A medium wasprepared containing per liter 20 grams of dextrose and 20 grams of cornsteep liquor containing 12 grams of solid material. This medium wasadjusted to a pH of 6.5 by the addition of sodium hydroxide and thensterilized. To 12 liters of such sterilized medium was added vegetativemycelium growth of Cunninghamella blakesleeana ATCC 9245, previouslycultivated from spores. This medium was then incubated for 48 hours at24 degrees centigrade. Thereupon was added 12 grams of3fi-hydroxy-5-androsten-17-one and the incubation continued at 26degrees Centigrade, under stirring and aeration for a period of 48hours. Thereupon the fermentation mixture was filtered. The resultingcake was extracted with three four-liter portions of acetone which wereadded to the aqueous beer and the volume of the beer was reduced to onehalf, at 50 degrees centigrade under reduced pressure. To this mixture,approximately 12 liters, was now added 3 liters of acetone and thissolution was filtered and then extracted five times with three literportions of Skellysolve B hexanes to remove lipids resulting from thefermentation. The thus-obtained mixture was extracted four times with5-liter volumes of ethylene dichloride. The ethylene dichloride extractswere combined, dried over anhydrous sodium sulfate and evaporated. Thethus-produced residue was three times recrystallized from methanol andSkellysolve B hexane to give 35,11fl-dihydroxy-S-anclrosten-17-one.

7 PREPARATION 6 3,3,1 1 [3-dihydroxy-6-methyl-5 -andrsten-1 7-0ne In thesame manner as shown in Preparation 5, 3(3-hydroxy-6-methyl-S-androsten-17-one is submitted to fermentation withCunniltghamella blakesleeana and the fermentation mixture is extractedwith water-immiscible organic solvents such as ethylene dichloride,methylene chloride, ether, benzene and the like to give3,8,11,8-dihydroxy-6-methyl-5-androsten-17-one which is purified byeither recrystallization from methanol, ethanol or mixtures of methanoland ethanol and hydrocarbons such as Skellysolve B hexanes, heptane, orthe like.

7 PREPARATION 7 I 3B-mercapt0-11fl-hydroxy-6-methyl-S-aizdrosten-l7-0110 In the same manner given in Preparation 4,3,8,11fl-dihydroxy-6-methyl-S-androsten-17-one is converted to the3fi-p-toluenesulfonate which by treatment with thiourea and pyridineproduces the 3B-isothiuronium p-toluenesulfonate of35,11,B-dihydroxy-6-methyl-5-androsten-17-one. Treatment of theisothiuronium toluenesulfonate with sodium hydroxide solution gave the3Ii-mercapto-11flhydroxy-6-methyl-5-androsten-17-one.

In the same manner as shown in Preparation 7, the3fi-mercapto-llfl-hydroxy-S-androsten-17-one was prepared.

EXAMPLE 1 3B- (Z-diethylaminoethoxy -5-andr0stcn-17,8-ol hydrochloride Asolution of 6.0 grams of 35-(Z-diethylaminoethoxy)- 5-androsten-17-onehydrochloride in Water was made basic with solid sodium bicarbonate andthe precipitate taken up in ether-benzene. The free base was obtained asan oily solid upon evaporation of the solvent in vacuo.

The thus-obtained free base, dissolved in 50 milliliters oftetrahydrofuran, was added to a well stirred suspension of 2.0 grams oflithium aluminum hydride in milliliters of tetrahydrofuran. The mixturewas heated for 6 hours under reflux, then allowed to cool and the excessreagent destroyed with ethyl acetate. Water and ether were then added.The organic layer was separated, washed several times with water, driedover anhydrous sodium sulfate and evaporated to give a residue. Thisresidue was taken up in ether and the ether solution was thereuponextracted with 0.5 normal aqueous hydrochloric acid. The solution of theaminoether hydrochloride in the aqueous acid was separated and washedwith chloroform. The combined chloroform washings were evaporated togive 4.85 grams of crude product which was twice recrystallized fromchloroform-ethyl acetate to give an analytical sample of3,8-(2-diethylaminoethoxy)-5-androsten-17B-ol hydrochloride of meltingpoint 258 to 261 degrees.

Analysis.Calcd. for C H ClNO C, 70.47; H, 10.41; N, 3.29. Found: C,69.58; H, 10.39; N, 3.31.

EXAMPLE 2 3,a- (Z-diethylaminoeth oxy 7u-methyl-S-androsten- 17,8-01

A solution of 4.15 grams of 3,8-(2-diethylaminoethoxy)-5-androsten-17-one in 100 milliliters of tetrahydrofuran was added to 40milliliters of a 3 molar methylmagnesium bromide solution in ether. Theresulting solution was heated under reflux for two hours and thenallowed to stand at room temperature for 15 hours. The excess reagentwas destroyed with water and ether was added. The organic layer wasseparated, washed well with water and dried with anhydrous magnesiumsulfate. The solid which remained when the solvent was distilled wasrecrystallized twice from aqueous acetone to yield 2.30 grams of3/3-(Z-diethylaminoethoxy)-l7amethyl-S-androsten-175-01 of melting point118 to 120 C.

8 Analysis.-Calcd. for C H NO AH O: C, 76.51; H, 11.24; N, 3.43. Found:C, 76.37; H, 11.27; N, 3.58.

Further recrystallization from benzene and drying of the crystals invacuo at C. gave water free material.

EXAMPLE 3 3 (3- (Z-di ethy laminoethoxy -1 7 a-ethyny l-5 -andr0sten- 1-01 hydrochloride Acetylene was allowed to bubble through an ice-coldether-free solution of methylmagnesium bromide in milliliters oftetrahydrofuran for a period of 45 minutes. To this solution there wasadded a solution of 3 8-(2- diethylaminoethoxy)-5-androsten-17-one in100 milliliters of tetrahydrofuran. After 15 hours of heating underreflux, the mixture was allowed to cool and the excess reagent destroyedby adding water. Ether was thereupon added and the organic layer Washedwell with water, followed by 0.5 N hydrochloric acid. The acid wash wasthen extracted with 600 milliliters of methylene chloride. The methylenechloride solution was evaporated and the resulting solids, 3.70 grams,was recrystallized twice from ethanol-ethyl acetate to yield 2.41 gramsof 3B-(Z-diethylaminoethoxy)-17u ethynyl 5-androsten- -01 hydrochlorideof melting point 251.5 to 253 de grees.

Some of this sample was recrystallized from ethanol to give a pureanalytical sample of melting point 258- 260 C. However, the infraredspectrum of this sample showed it to be an ethanol solvate. Analysis forthe ethanol solvate is as follows:

Analysis.-Calcd. for C27H44C1NO2.C2H5OHZ C, 70.21; H, 10.15; N, 2.82.Found: C, 70.26; H, 10.05; N, 3.47.

Treating 3/3-(2 diethylaminoethoxy)-17a-ethynyl-5- androsten-l7t3-olhydrochloride in aqueous solution with potassium carbonate yields thefree base, 3fi-(2-diethylaminoethoxy)-17a-ethynyl-5-androsten-176-01which is recovered from the aqueous mixture by extraction withwater-immiscible solvents and evaporation of the solvent.

EXAMPLE 4 36- (Z-diethy laminoethoxy) -5-andr0sten-1 7 -one N-oxidehydrochloride To a solution of3B-(Z-diethylaminoethoxy)-5-androsten-l7-one hydrochloride (3.5 grams),dissolved in 20 milliliters of methanol, was added 10 milliliters of a 5percent solution of sodium hydroxide in methanol. After swirling for 5minutes the mixture was filtered and the filtrate evaporated to drynessunder vacuum. The residue was dissolved in 100 milliliters of methylenedichloride which was then washed with three 25 milliliter portions ofwater. The methylene dichloride phase was filtered and then evaporatedto dryness under vacuum, yielding 2.34 grams of the free base of thestarting hydrochloride. This white solid material was dissolved in 10milliliters of ethanol, cooled in an ice bath and 5 milliliters of 30percent hydrogen peroxide solution added. After standing at about 25degrees for 18 hours, the excess hydrogen peroxide was destroyed byportionwise addition of 500 milligrams of platinum oxide catalyst.Filtration and evaporation of the filtrate gave a white solid which wasdissolved in ether. Hydrogen chloride gas was bubbled into this solutionand the white solid which precipitated was collected, dried andrecrystallized twice from acetone to give 3/3-(Z-diethylaminoethoxy)-5-androsten-17-one N-oxide hydrochloride of melting point 156 to 159.

Analysis-Called. for C H ClNO C, 68.23; H, 9.62; N, 3.18; Cl, 8.06.Found: C, 68.27; H, 9.78; N, 3.27; Cl, 8.16.

9 EXAMPLE 3,6- (Z-diethylamirzoethoxy -5a-andr0stan-1 7-onehydrochloride 318-(Z-diethylaminoethoxy)-5-androsten 17-onehydrochloride (1.1 grams) was dissolved in 200 milliliters of methanoland reduced in a Parr Hydrogenator at 30 to 50 psi. of hydrogen pressureusing about 1 gram of 5 percent palladium on carbon as reductioncatalyst. After one hour of the theoretical amount of hydrogen had beentaken up, the reaction solution was filtered to remove the catalyst andthe filtrate evaporated to dryness. The solid residue was recrystallizedfour times from a mixture of acetone-Skellysolve B hexanes to give3,8-(2- diethylaminoethoxy)-5u-androstan-17-one hydrochloridemonohydrate of melting point 164 to 165 degrees, with a yield of 500milligrams.

Analysis.Calcd. for C H NO HCLH O: C, 67.76; H, 10.24; N, 3.16; CI,8.00. Found: C, 67.81; H, 10.12; N, 3.29; Cl, 8.17.

Further heating to 60 C. in a vacuum desiccator resulted in theanhydrous material, Sfi-(Z-diethylaminoethoxy)-5ot-androstan-17-onehydrochloride.

EXAMPLE 6 3 ,8- (Z-diethy laminoethylth io -5 -androsten-1 7-0nehydrochloride A mixture of 0.35 mole of 3/3-mercapto-5-androsten-17-one, 100 milliliters of ethylene glycol, 1500 milliliters of benzeneand 2 grams of p-toluenesulfonic acid were heated and refluxed for fivehours. The water produced is removed from the reaction mixture by use ofa water trap. The reaction mixture was then cooled to 30 degrees, washedwith 200 milliliters of 5 percent potassium bicarbonate solution, driedover anhydrous sodium sulfate and finally 200 milliliters of benzene wasdistilled from this mixture to complete the drying process. To the drybenzene solution was added 0.37 mole of butyllithium, dissolved inhexane, followed after minutes by the addition of 0.38 mole ofdiethylaminoethyl chloride. The reaction mixture was heated at refluxtemperature for 24 hours, cooled to 25 degrees, diluted with 1 liter ofether and extracted with three 800 milliliter portions of dilutehydrochloric acid (80 milliliters of 37 percent hydrochloric aciddiluted to 800 milliliters). The aqueous extract was washed once with800 milliliters of ether. The organic extracts were combined, dried overanhydrous sodium sulfate and evaporated to give the dry residue of theunreacted material.

The aqueous acidic phase was extracted with three 500- milliliterportions of methylene dichloride and these extracts were combined, driedand evaporated and the residue twice recrystallized from acetone togive, in 33 percent yield, 35-(Z-diethylaminoethylthio)-5-androsten-l7-one hydrochloride of melting point 186 to 189 degrees and rotation [11]plus 8 degrees.

Analysis.--Calcd. for C H ClNOS: C, 68.22; H, 9.62; N, 3.18; S, 7.29;CI, 8.06. Found: C, 67.78; H, 9.56; N, 3.23; S, 7.18; CI, 8.12.

EXAMPLE 7 3 5- (Z-diethylam inoethylthio -5 -androsten-l 7-one N -oxidehydrochloride To a mixture of 0.38 mole of diethylaminoethyl chloride,dissolved in 250 milliliters of ethanol and cooled in an ice-bath, wasadded 125 milliliters of 30 ercent hydro gen peroxide. After standing atabout five degrees for 18 hours, the excess hydrogen peroxide wasdestroyed by the portion-wise addition of platinum oxide catalyst. Afterfiltration, the solvent was evaporated in vacuo to yield crudediethylaminoethyl chloride N-oxide.

This crude diethylaminoethyl chloride N-oxide was added to a benzenesolution of the lithium salt of 3,8- mercapto-S-androsten-l7-one17-ethylene ketal, prepared as in Example 6. The reaction mixture washeated at reflux for 24 hours, cooled to room temperature, diluted with1000 milliliters of ether and extracted with three portions of 750milliliters of hydrochloride acid (one part 37 percent hydrochloric acidand nine parts water). The aqueous extract was washed once with 750milliliters of ether. The aqueous acidic phase was extracted with three500-milliliter portions of methylene dichloride, the extracts werecombined, dried, evaporated and the thusobtained residue twicerecrystallized from ethanol to give 3 8- Z-diethylaminoethylthio)-5-androsten-17-one N-oxide hydrochloride.

In the same manner given in Example 7, the N-oxides ofdimethylaminoethyl chloride, diethylaminopropyl chloride,dimethylaminopropyl chloride, diethylaminobutyl chloride,dimethylaminobutyl chloride, diethylaminopentyl chloride,dimethylaminopentyl chloride, diethylaminohexyl chloride,dimethy-laminohexyl chloride can be made, which upon reaction with aselected lithium salt of 3,8- rnercapto-S-androsten-17-one 17-ketal, asshown in Example 7, result in the corresponding3B-(2-dialkylaminoalkylthio)-5-androsten-17-one N-oxide hydrochloride.

Thus from:

(a) 3fl-mercapto-5-androsten-l7-one with diethylaminopropyl chlorideN-oxide was obtained 3,8-(3-diethylaminopropylthio)-5-androsten-l7-oneN-oxide hydrochloride.

(b) 3fl-mercapto-5-androsten-17-one with diethylaminobutyl chlorideN-oxide was obtained 3/3(4-diet-hylaminobutylthio)-5-androsten 17 oneN-oxide hydrochloride.

(c) 3 3-mercapto-5-androsten-17-one with diethylaminopentyl chlorideN-oxide was obtained 35-(5-diethylaminopentylthio)-5-androsten-17-one Noxide hydrochloride.

(d) 3fi-mercapto-5-androsten-17-one with diethylaminohexyl chlorideN-oxide was obtained 3,8-(6-diethyl- .aminohexylthio)-5-androsten l7 oneN-oxide hydrochloride.

(e) 3B-mercapto-S-androsten-l7-one with dimethylaminobutyl chlorideN-oxide was obtained 3B-(4-ditmethylaminobutylthio)-5-androsten l7 oneN-oxide hydrochloride.

(f) 3,G-mercapto-S-androsten-l7-one with dimethylaminopentyl chlorideN-oxide was obtained 3fi-(5-dimethylaminopentylthio)-5-androsten-l7-oneN oxide hydrochloride.

(g) 3fl-mercapto-5-androsten-17-one with dimethylaminohexyl chlorideN-oxide was obtained 3fl-(6-dimethylaminohexylthio)-5-androsten l7 oneN-oxide hydrochloride.

(h) SB-mercapto-S-androsten-l7-one with morpholinylbutyl chlorideN-oxide was obtained 3fi-(4-morpholinylbutylthio)-5-androsten-17-oneN-oxide hydrochloride.

(1) SB-mercapto-l lfi-hydroxyl-S-androsten-l7-one with diethylaminoethylchloride N-oxide was obtained 36-(2- diethylaminoethylthio) 11Bhydroxyl-5-androsten-17- one N-oxide hydrochloride.

(j) 3fl-mercapto-l lB-hydroxyl-S-androsten-l7-one withdiethylaminopropyl chloride N-oxide was obtained 3,8-(3-diethylaminopropylthio) 11,8 hydroxyl-S-androsten- 17-one N-oxidehydrochloride.

(k) Sfi-mercapto-llfl-hydroxyl-S androsten-17-one with diethylaminobutylchloride N-oxide was obtained 318- (4-diethylaminobutylthio) 11Bhydroxy-S-androstenl7-one N-oxide hydrochloride.

(1) 3,8-mercapto-11,8-hydroxyl-5 androsten-17-one withdiethylaminopentyl chloride N-oxide was obtained 3,8-(S-diethylaminopentylthio) 1lfl-hydroxyl-S-androsten- 17-one N-oxidehydrochloride.

(in) BB-mercapto-llfi-hydroxyl-S androsten-l7-one withdimethylaminobutyl chloride N-oxide was obtained 3,8-4-dirnethylarninobutylthio) -1 1 fi-hydroxyl-S-androstem 17-one N-oxidehydrochloride.

(n) 3fl-mercapto-l1;8-hydroxyl-5 androsten-17-one withdimethylaminohexyl chloride N-oxide was obtained 31i-(6-dirnethylaminohexylthio) -1 lfl-hydroxyl-S-androstenl7-0ne N-oxidehydrochloride.

() 3B-mercapto-1lfl-hydroxyl-S androsten-17-one with morpholinylhexylchloride N-oxide was obtained 35-(6- morpholinylhexylthio)-1lfi-hydroxylandrosten-17- one N-oxide hydrochloride.

(p) 3 3-mercapto-6-methyl 5 androsten-17-one with diethylaminoethylchloride N-oxide was obtained 3 8-(3- diethylaminoethylthio)-6-methyl-5audrosten-17-one N- oxide hydrochloride.

(q) 3fi-mercapto-6-methyl 5 androsten-17-one with diethylaminohexylchloride N-oxide was obtained 3 8-(6- diethylaminohexylthio)-6-methy1 5androsten-17-one N-oxide hydrochloride.

(r) 3B-mercapto-6-methyl-S-androsten-17-one with morpholinylhexylchloride N-oxide was obtained 3,8-(6-morpholinylhexylthio)-6-methyl-5-androsten-17-0ne N- oxidehydrochloride.

(s) 3/3-n1ercapto-6-rnethyl-1lp hydroxy-5-androsten-17- one withdiethylaminoethyl chloride N-oxide was obtained 35-(2diethylaminoethylthio) 6 methyl-11,8- hydroxy-S-androsten-17-one N-oxidehydrochloride.

(t) 3/3-mercapto-6-rnethyl-11B hydroxy-5-androsten-17- one withdiethylaminobutyl chloride N-oxide was obtained 35-(4diethylaminobutylthio) 6 methyl-11,8- hydroxy-S-androsten-17-one N-oxidehydrochloride.

(u) 3,6-mercapto-6-rnethyl-1lfl-hydroxy-S-androsten 17- one withdiethylaminohexyl chloride N-oxide was obtained 3B-( 6diethylaminohexylthio) 6 methyl-11,8- hydroxy-S-androsten-17-one N-oxidehydrochloride.

(v) 3,8-mercapto-6-methyl-1lfi-hydroxy-S-androsten 17- one withdimethylaminohexyl chloride N-oxide was obtained 3 8 (6dimethylaminohexylthio)-6-methyl-11flhydroxy-S-androsten-17-one N-oxidehydrochloride.

(w) 3fl-rnercapto-6-methyl-l1,8-hydroxy-5-androsten 17- one withmorpholinylhexyl chloride N-oxide was obtained 36-(6-morpholinylhexylthio) 6-methyl-1lfi-hydroxy-5-androsten-17-oneN-oxide hydrochloride.

EXAMPLE 8 3,8-(3-diethylaminoprop0xy) -5-andr0sten-17-one hydrochlorideEXAMPLE 9 3 ,8- (2 -dimethylamin0ethoxy -5 -andr0sten-1 7 -onehydrochloride In the same manner given in Example 6, 3fi-hydroxy-S-andr0sten-17-one was converted with dirnethylaminoethyl chloride to3B-(Z-dimethylaminoethoxy)-5-androsten-17- one of melting point 232 to234 degrees.

Analysis.Calcd. for C23H33C1N02'H201 C, H, 10.22; N, 3.38; Cl, 8.57.Found: C, 69.47; H, 9.50; N, 3.56; Cl, 8.99.

EXAMPLE 10 3B- (Z-morpholinylethoxy -5-andr0sten-1 7-one hydrochlorideIn the same manner given in Example 6, 3fi-hydroxy-5- androsten-l7-onewas converted with morpholinylethyl chloride to3,8-(2-rnorpholinylethoxy) -5-androsten-17-one hydrochloride which whenrecrystallized from ethyl ace tate melted at 216 to 218 degreescentigrade with rotation [ab of plus 12 degrees in chloroform.

12 Analysis.-Calcd. for C H CINO C, 68.54; H, 9.20; N, 3.20; Cl, 8.10.Found: C, 67.91; H, 9.15; N, 3.35; CI, 8.15.

EXAMPLE 11 3 ,8- 2-diethylaminoethoxy -5 u-androstan-l 7 -one, N -0xidc,hydrochloride In the same manner as shown in Example 4,3fi-(2-diethylaminoethoxy) -5a-androstan 17 one hydrochloridemonohydrate was converted to 3B (2diethylaminoethoxy)-5ot-androstan-17-one N-oxide, hydrochloride in 43percent yield with a melting point of 151 to 153 degrees and rotation[ab of plus 47 degrees in chloroform.

Analysis.--Calcd. for C H CINO C, 67.92; H, 10.03; N, 3.17; Cl, 8.02.Found: C, 67.68; H, 10.16; N, 3.19; Cl, 8.09.

EXAMPLE 12 In the same manner given in Example 6, other 3-arninoethersand 3-thioarninoethers are obtained by converting a selected 3fi-hydroxyor 3B-mercapto-5-androsten-17-one to its respective l7-ketal, treatingthe ketal with an alkali metal metathetically active reagent, e.g.,butyl lithium, sodium or potassium hydride, sodium trip'henylmethane andthe like, and thereupon with a selected N-substituted amino-alkylchloride. Thus from:

(a) 3/3-hydroxy-5-androsten-l7-one with diethylarninobutyl chloride wasobtained 3,8-(4-diethylaminobutoxy)-5- androsten-17-one hydrochloride.

(b) 3,8-hydroxy-S-androsten-l7-one with diethylaminopentyl chloride wasobtained 3B-'(S-diethylaminopentoxy)-5-androsten-l7-one hydrochloride.

(c) Elfl-hydroxy-S-androsten-l7-one with diethylaminohexyl chloride wasobtained 3B-(6-diethylaminohexyloxy) -5-androsten-17-one hydrochloride.

((1) 3B-hydroxy-5-androsten-17-one with dimethylaminobutyl chloride wasobtained 3B-(4-dimethylaminobutoxy)-5-androsten-17-one hydrochloride.hexyl chloride was obtained3,8-(6-morpholinylhexyloxy)-5-androsten-17-one hydrochloride.

(e) 3 B hydroxy 5-androsten-l7-one with morpholinylbutyl chloride wasobtained 3,8-(4-rnorpholinylbutoxy)- 5-androsten-17-one hydrochloride.

(f) 3,8-hydroxy-5-androsten-17-one with dimethylaminopentyl chloride wasobtained 3fi-(5-dimethylaminopentoxy)-5-androsten-17-one hydrochloride.

(g) 3 3 hydroxy 5-androsten-17-one with morpholiny1- pentyl chloride wasobtained 3,8-(5-morpholinylpentoxy)-5-androsten-17-one hydrochloride.

(h) 3B-hydroxy-5-androsten-17-one with dimethylaminohexyl chloride wasobtained 3,8-(6-dimetl1ylaminohexyloxy)-5-androsten-17-onehydrochloride.

(i) 3 B hydroxy 5-androsten-17-one with morpholinyl- (j) 33-mercapto-S-androsten-l7-one with diethylaminopropyl chloride wasobtained 3fi-(3-diethylaminopropylthio)-5-androsten-17-onehydrochloride.

(k) 3/3-rnercapto-5-androsten-17-one with diethylaminobutyl chloride wasobtained 3/3-(4-diethylaminobutylthio -5-androsten-17-one hydrochloride.

(1') 3Bmercapto-S-androsten-l7-one with diethylaminopentyl chloride wasobtained 3,8-(S-diethylarninopentylthio)-5-androsten-17-onehydrochloride.

(in) 3B-mercapto-5-androsten-17-one with diethylaminohexyl chloride wasobtained 3 8-(6-diethylarninohexylthio)-5-androsten-17-onehydrochloride.

(11) 3B mercapto-S-androsten-17-one with dimethylaminobutyl chloride wasobtained 3,8-(4-dimethylaminobutylthio)-5-androsten-17-onehydrochloride.

(0) 3/3 -mercapto-S-androsten-17-one with dimethylaminopentyl chloridewas obtained 3 8-(5-dimethylaminopentylthio)-5-androsten-l7-onehydrochloride.

(p) 3B-mercapto-S-androsten-17-one with dimethylaminohexyl chloride wasobtained 3fl-(6-dimethylaminov hexylthio)-5-androsten-l7onehydrochloride.

(q) 3,8-mercapto-S-androsten-17-one with morpholinyl- 13 butyl chloridewas obtained 35-(4-morpholinylbutylthio)-5-androsten-17-onehydrochloride.

(r) 35-mercapto-S-androsten-l7-one with morpholinylpentyl chloride wasobtained 35-(5-morpholinylpentylthio)-5-androsten-l7-one hydrochloride.

(s) 35-mercapto-S-androsten-17-one with morpholinylhexyl chloride wasobtained 35(6-morpholinylhexylthio)-5-androsten-l7-one hydrochloride.

Example 13 In the same manner given in Examples 6 and 7, 11-oxygenated3-arnino ethers and ll-oxygenated 3-aminothioethers are obtained byconverting a selected 35,115-dihydroxy or35-rnercapto-l15-hydroXy-5-androsten-17-one to its respective ketal,treating the ketal with butyl lithium and thereupon with a selectedN-substituted amino alkyl chloride. Thus from:

(a) 35,115 dihydroxy-S-androstem17-one with diethylaminoethyl chloridewas obtained 35-(2-diethylaminoethoxy) 115 hydroxy-S-androsten17-onehydrochloride.

(b) 35,115 dihydroxy-S-androsten-l7-one with diethylaminopropyl chloridewas obtained 35-(3-diethy1aminopropoxy) 115-hydr0xy-5-androsten-17-onehydrochloride.

(c) 35,115 dihydroxy-S-androsten-17-one with diethylaminobutyl chloridewas obtained 35-(4-diethylaminobutoxy) 1=15 hydroxy-S-androstend7-onehydrochloride.

(d) 35,115 dihydroxy-S-androsten-17-one with diethylaminopentyl chloridewas obtained 35-(5-diethylaminopentoxy) 115-hydroXy-5-androsten-17-onehydrochloride.

(e) 35,115-dihydroxy-S-androsteml7-one with diethylaminohexyl chloridewas obtained 35-(6-diethylaminohexyloxy)-115-hydroxy-5-androsten-17-onehydrochloride.

(f) 35,115-dihydroXy-5-androsten-17-0ne with dirnethylaminobutylchloride was obtained35-(4-dimethylaminobutoxy)-115-hydroxy-5-androsten-17-one hydrochloride.

(g) 35,115 dihydroxy-S-androsten-17-one with morpholinylbutyl chloridewas obtained 35-(4-morpholinylbutoxy) 115 hydroxy-S-androsten-17-onehydrochloride.

(h) 35,115-dihydroXy-5-androsten-17-one with dirnethylaminopentylchloride was obtained 35-(5-dirnethylaminopentoxy) 115hydroxy-S-androsten-17-one hydrochloride.

(i) 35,115- dihydroXy5-androsten-17-one with morpholinylpentyl chloridewas obtained 35-(5-morpholinylpentoxy) 115-hydroXy-5-androsten-17-onehydrochloride.

(j) 35,115-dihydroXy-5-androsten17-one with dirnethylaminohexyl chloridewas obtained 35-(6-dimethylaminohexyloxy) 115 hydroxy-S-androsten-17-onehydrochloride.

(k) 35,115-dihydroXy-5-androsten-l7-one with morpholinylhexylchloridewas obtained 35-(6-morphovlinylhexy1oXy)-1 15-hydroxy-5-androsten-17-onehydrochloride.

(1) 35-rnercap'to-115-hydroXy-5-androsten-17-one with diethylaminoethylchloride was obtained 35-(2-diethylaminoethylthio -115-hydroxy-5-androsten-17-one hydrochloride.

(in) 35-mercapto-115-hydroxy-5-androsten-17-one with diethylaminopropylchloride was obtained 35-(3-diethylaminopropylthio)-115-hydroxy-5-androsten- 17-one hydrochloride.

(n) 35-mercapto-115-hydroxy-5-androsten-17-one with diethylaminobutylchloride was obtained 35- (4- diethylaminobutylthio -115-hydroXy-5-androsten- 17-one hydrochloride.

() 35-rnercapto-115-hydroXy-S-androsten-17-0ne with diethylaminopentylchloride was obtained 35-(5- 14 diethylaminopentylthio -1 15-hydroxy-5-androstenl7-one hydrochloride.

(p) 3 5-mercapto-1 15-hydroXy-5-androsten-17-one with diethylaminohexylchloride was obtained 35- 6-diethylarninohexylthio -1 15-hydroxy-5-androsten-l7-one hydrochloride.

(q) 35-mercapto-1 15-hydroXy-5-androsten-17-one with dimethylaminobutylchloride was obtained 3 5- (4-dimethylaminobutylthio -1 15-hydroxy-5-androsten-17-one hydrochloride.

(r) 35-mercapto-115-hydroxy-5-androsten-17-one with dimethylaminopentylchloride was obtained 35-(5-dimethylaminopentylthio)-115-hydroxy5-androsten-l7-one hydrochloride.

(s) 35-mercapto-ll5-hydroxy-5-androsten-l7-one with dimethylaminohexylchloride was obtained 35-(6-dimethylaminohexylthio -l15-hydroxy-S-androsten- 17-one hydrochloride.

(t) 35-rnercapto-115-hydroxy-5-androsten-17-one with morpholinylbutylchloride was obtained 35-(4-morpholinylbutylthio -115-hydroxy-5-androster1- l7-one hydrochloride.

(u) 35-rnercapto-1l5-hydroxy-5-androsten-17-one with morpholinylpentylchloride was obtained 35-(5- n1 orpholinylpentylthio -115-hydroXy-5-androste11- 17-0ne hydrochloride.

(v) 35-rnercapto-115-hydroxy-5-androsten-17-one with morpholinylhexylchloride was obtained 35-(6-morpholinylheXylthio)-l15-hydroXy-5-androsten- 17-one hydrochloride.

EXAMPLE 14 In the same manner given in Examples 6 and 7, 3-arnino-6-methyl ethers and thioethers are obtained by convertingselected 3 5-hydroxy-6-methylor 35-rnercapto- 6-methyl 5androsten-17-ones, 35,115-dihydroxy-6- methylor 35-rnercapto-6-rnethyl-l15-hydroXy-5-androsten-17-ones to its respective ketals,treating the kctals with butyl lithium and thereupon with a selectedN-substituted amino alkyl chloride. Thus from:

(a) 35-hydroXy-6-rnethyl-S-androsten-17-one with diethylaminoethylchloride was obtained 35-(2-diethylaminoethoxy)-6-methyl-5-androsten-l7-one hydrochloride.

(b) 35-hydroxy-6-methyl-5-androsten-17-one with diethylaminobutylchloride was obtained 35-(4- diethylaminobutoxy)-6-methyl-5-androsten-17- one hydrochloride.

(c) 35hy droxy-6-methyl-5-androsten-l7-one with diethylaminohexylchloride was obtained 35-(6- diethylaminohexylo-Xy 6-methyl-5-androsten17-one hydrochloride.

((1) 35-hydroxy-6-methyl-5-androsten-17-one with dirnethylaminobutylchloride was obtained 35-(4- dimethylarninobutoxy6-rnethyl-5-androstenl7-one hydrochloride.

(e) 35-hydroxy-G-methyl-S-androsten-17-one with morpholinylethylchloride was obtained 35-(4- morpholinylethoxy) -6-methyl-5-andr0sten-17-one hydrochloride.

(f) 35-hydroxy-6-rnethyl-5-androsten-17-one with dimethylaminohexylchloride was obtained 35-(6- dimethylaminohexyloxy)-6-methyl-5-androsten- 17-one hydrochloride.

(g) 35-rnercapto-6-methy1-5-androsten17-one with diethylaminoethylchloride was obtained 35-(3- diethylaminoethylthio)-6-methyl-5-androstenl7-one hydrochloride.

(h) 35-n1ercapto-6-methyl-5-androsten-17-0ne with diethylaminobutylchloride was obtained 35-(4- diethylaminobutylthio 6-methyl-5-androsten-17-one hydrochloride.

(i) 35-mercapt0-6-methyl-5-androsten-17-one with diethylaminohexylchloride was obtained 35-(6- diethylaminohexylthio-6-methyl-5-androsten- 17-hydrochloride.

(j) 36-mercapto-G-methyl-S-androsten-17-one with dimethylaminohexylchloride was obtained 36- (6-dimethylaminohexylthio -6-methy15-androsten- 17-one hydrochloride.

(k) 36-mercapto-6-methyl-5-androsten-17-one with morpholinylhexylchloride was obtained 36-(6- morpholinylhexylthio)-6-methyl-5-androsten- 17-one hydrochloride.

(1) 36,116-dihydroxy-6-methyl-5-androsten-17-one with diethylaminoethylchloride was obtained 36-(4- diethylaminoethyl) -6-methyl-116-hydroxy-5- androsten-17-one hydrochloride.

(m) 36,116-dihydroxy-6-methyl-S-androsten-17-one with diethylaminohexylchloride was obtained 36- (6-diethylaminohexyloxy) -6-methyl- 116-hydroxyandrosten-17-one hydrochloride.

(11) 36,1 1,B-dihydroxy-6-methyl-5-androsten-17-one withdimethylaminobutyl chloride was obtained 36- 4-dimethylaminobutoxy-6-methyl-1 16-hydroxy- 5-androsten-17-one hydrochloride.

( o) 36,116-dihydroxy-6-methyl-5-androsten-17-one withdimethylaminohexyl chloride was obtained 3 6- (6-dimethylaminohexyloxy-6-methyl-1 16- hydroxy-S-androsten-17-one hydrochloride.

(p) 36,116-dihydroxy-G-methyI-S-androsten-17-one with morpholinylhexylchloride was obtained 3 6- 6-morpholinylhexyloxy -6-methyl-1 16-hydroxy-5-androsten-17-one hydrochloride.

(q) 3 6-mercapto-6-methyl-1 16-hydroXy-5-androsten- 17-one withdiethylaminoethyl chl-oride was obtained 3 6- Z-diethylaminoethylthio6-methyl-1 16- hydroxy-S-androsten-l7-one hydrochloride.

(r) 3 6-mercapto-6-methyl-1 16-hydroXy-5-androsten 17-one withdiethylaminobutyl chloride was obtained36-(4-diethylaminobutylthio)-6-methyl- 116-hydroxy-5-androsten-17-onehydrochloride.

(s) 36 mercapto-6-methyl-116-hydroXy-5-androsten-17- one withdiethylaminohexyl chloride was obtained 36- (6 diethylaminohexylthio) 6methyl-116-hydroxy-5- androsten-17-one hydrochloride.

(t) 36 mercapto-6-methyl-116-hydroxy-5-androsten-l7- one withdimethylaminohexyl chloride was obtained 36 (6 dimethylaminohexylthio) 6methyl-116-hydroxy-5-androsten-17-one hydrochloride.

(u) 36 mercapto-6-methyl-116 hydroxy-5-androsten-17- one withmorpholinylhexyl chloride was obtained 36- (6 morpholinylhexylthio) 6methyl-116-hydroxy-5- androsten-17-one hydrchloride.

The amino ethers and the amino thioethers of EX- amples 12, 13 and 14obtained as hydrochlorides can be obtained as free bases by adding tothe aqueous solution of the amino ether hydrochloride or the aminothioether hydrochloride a base such as sodium hydroxide, sodiumbicarbonate, potassium hydroxide, potassium carbonate and bicarbonateand the like and extracting the aqueous mixture with water-immisciblesolvent such as ether, benzene, methylene chloride, hexanes and thelike. The thus-obtained solution is further washed with water, thendried and evaporated, giving the amino ether as free base.

EXAMPLE 15 36- (Z-diethylaminoethylthio) 7ot-methyl-5- androsten-J 76-01 In the same manner given in Example 2, two grams of36-(Z-diethylaminoethylthio)-5-androsten-17-one in tetrahydrofuran wasadded to 40 milliliters of a 3 molar methyl magnesium bromide solutionin ether. The resulting solution was heated under reflux for two hoursand allowed to stand over night for a period of about hours. Thereuponthe excess reagent was destroyed with water and the aqueous reactionmixture extracted with ether. The ether solution was washed severaltimes with water, then evaporated and the solids obtained recrystallizedfrom aqueous acetone to yield36-(2-diethylaminoethylthio)-17a-methyl-5-androsten-176-01.

1 e EXAMPLE 16 3 6- Z-d z'ethylaminoethyl t/z i0) -1 7 a-ethynyl-5-andr0sten- 176-0l hydrochloride In the same manner given in Example 3,acetylene was allowed to bubble through an ice-cold ether-free solutionof methyl magnesium bromide in tetrahydrofuran. To this solution wasthen added 36-(2-diethylaminoethylthio)-5-androsten-17-one intetrahydrofuran. After heating for 15 hours, the excess reagent wasdestroyed by the addition of water and the reaction mixture extractedwith ether. The ether solutions were washed with water, then withhydrochloric acid and the aqueous acid wash was then extracted with 600milliliters of methylene chloride. The methylene chloride solution wasevaporated and the resulting solids recrystallized from ethanol andethyl, acetate to yield 36-(Z-diethylaminoethylthio)-17a-ethynyl-5-androstcn-l76-0l hydrochloride.

EXAMPLE 17 36- (Z-diethylaminethoxy -6,1 t-diI716fllyl-5andr0sten-176-0l In the same manner given as in Example 15, from 36-(2-diethylaminoethoxy)-6-methyl-5-androsten-l7-one with methyl magnesiumbromide was obtained36-(2-diethylaminoethoxy)-6,l7ot-dimethyl-S-androsten-176-01.

EXAMPLE 18 36-(2-diethylamin0eth0xy -6,1 7a-dimethyl-1]6,1 76-dillydroxy-S-androsten In the same manner given in Example 15,36-(2-diethylaminoethoxy)-6-methyl-5-androsten-17-one is treated withmethyl magnesium iodide to give36-(2-diethylaminoethoxy)-6,17a-dimethyl-116,176-dihydroxy-S-androsten.

EXAMPLE 19 36- (Z-diethylaminoerhylthio 6,] 7a-dimethyl-116J 76-dihydroxy-S-androsten In the same manner given in Example 15,36-(2-diethylaminoethylthio)-6-methyl-116-hydroXy-5-androsten 17- onegave with methyl magnesium iodide 36-(2-diethylaminoethylthio) 617a-din1ethyl-116,176-dihydroXy-5- androsten.

EXAMPLE 20 Substituting in Example 15, the starting steroid with 36- (2diethylaminoethylthio) 6 methyl-l16-hydroxy 5- androsten-17-one resultsin the production of 36-(2-diethylaminoethylthio)-6-methyl17ot-ethynyl-116,176 dihydroxy-S-androsten.

In the same manner as shown in Example 15, other l7ot-methyl steroidscan be prepared from the 3-amino and 3-thio amino 17-ketal ethers suchas, for example: 36- (3-diethylaminopropoxy )-17a-methyl-5-androsten- 36- 4-diethylaminobutyloxy 17ot-methyl-5 -androsten- 36-6-diethylaminohexyloxy 17a-methyl-5-androsten- 36-(Z-dimethylaminoethoxy 17u-methyl-5-androsten- 3 6-4-dimethylaminobutyloxy 1 7ot-methyl-5-androsten- 176-01-36-(5-dimethylaminopentyloxy)-17a-methyl-5-androsten- 36-Z-dimethylaminoethoxy -1 16,176-dihydroxy-17otmethyl-S-androstene;36-(3-diethylaminopropoxy)-6,17ot-dimethyl-5-androsten- 3 6-(4-diethylaminobutyloxy -6- 17ot-dimethyl-5-androsten- 36- 6-diethylaminohcxyloxy) -6, l7oz-dimethyl-5-androsten-l76-ol;36-(3-diethy1amin0propylthio)-17a-methyl-5-androstenl 7 3 ti-(4-diethylaminobutylthio 17a-methy1-5androsten- 17fi-ol;3[5-(6-dimethylaminohexylthio )-6,17a-dimethyl-1 113,175-

dihydroxy-S-androstene; 313- 4-dimethylaminobutylthio -6, 17a-dimethyl11,8,17,8-

dihydroxy-S-androstene; and the like.

EXAMPLE 21 A mixture is prepared consisting of milliliters of pyridine,5 milliliters of acetic anhydride and 1' gram of 3,8-(2-diethylaminoethoxy)17u-methyl 5 androsten 17B 01. This mixture wasallowed to stand at room temperature with occasional shaking for aperiod of 4 hours. The mixture was thereupon poured into ice-Water andallowed to stand over night. The material which had separated from itwas collected on filter paper, washed repeatedly with water and thenrecrystallized from methanol to give3fl-(2-diethylaminoethoxy)-17a-methyl-5-androsten 17/3- 01 17-acetate.

Replacing in Example 21, the acetic anhydride by propionic butyricvaleric, hexanoic, heptanoic, benzoic, phenylacetic or phenylpropionicanhydride or by an acid chloride such as ,B-cyclopentylpropionic, benzylchloride, lauroyl chloride, results in the production of thecorresponding l7-propioninate, butyrate, valerate, exanerate, octynrate,benzorate, phenyl-acetate, phenyl-propionate, B-cyclopendylpropionate,laurate and the like esters of the corresponding3B-(2-diethylaminoethoxy)- 17a-methyl-5-androsten-173-01.

In the same manner the acetate, propionates, butyrates, hexanoates,benzoates and other hydrocarbon carboxylic acid esters may be preparedof other Not-methyl and 17u-ethynyl, 17fi-hydroXy-5-androstenes havingan ether group such as Z-diethylaminopropoxy, Z-diethylaminobutyloxy,Z-diethylaminoethylthio, Z-diethylaminopropylthio, 2diethylaminohexylthio and the like.

EXAMPLE 22 3 ,9- (Z-diethylaminopro poxy -5 a-androstan-l 7-0nehydrochloride monohydrate In the same manner given in Example 5,hydrogenating 3,8-(Z-diethylaminopropoxy) -5-androsten-17 onehydrochloride in methanol with hydrogen in the presence of a palladiumcatalyst on a carbon carrier produces the3B-(2-diethylaminopropoxy)-5a-androstan-17-one hydrochloride.

In the same manner as shown in Example 5, other 3- amino and 3-aminothioethers of unsaturated steroid, as prepared in the foregoing examples,can be reduced to give the corresponding saturated 3-aminoand3-thioamino steroid ethers. Representative products such producedinclude:

3 ,9-(2-diethylaminoethoxy)-1 1 B-hydroxyandrostan- 17-onehydrochloride;

3/3-(Z-diethylaminoethoxy)-6-methyl-11B- hydroxyandrostan-17-onehydrochloride;

3/3-(3-diethylaminopropoxy)-1lfi-hydroxyandrostan- 17-one hydrochloride;

3 ,8- 3-diethylaminoprop oxy) -6ot-rnethyl-1 1,B-hydroxyandrostan-17-one hydrochloride;

3 B- (4-diethylaminobutyloxy -1 l B-hydroxyandrostan- 17-onehydrochloride;

35-(4-diethylaminobutyloxy)-6ot-methyl11,8-hydroxyandrostan-l7-onehydrochloride;

315'-(S-diethylaminopentyloxy)-1 lfl-hydroxyandrostan- 17-onehydrochloride;

3(3- (S-diethylaminopentyloxy) -6a-methyl-1 1 B-hydroxyandrostan-l7-onehydrochloride;

3 B-(6-diethylaminohexyloxy)-1 IB-hydroxyandrostan- 17-onehydrochloride; 7

3 5- fi-diethylaminohexyloxy) -6 a-methyl-l 1 fi-hydroxyandrostan-17-one hydrochloride;

3 ,6- 2-dimethylaminoethylthio -1 1 8-hydroxyandrostan- 17-onehydrochloride;

3,8-(Z-diethylaminoethylthio)-1lfi-hydroxyandrostan- 17-onehydrochloride;

3 5- 3-d-iethylaminopropylthio)-1 1 B-hydroxyandrostan- 17-onehydrochloride;

3 ,8- 6-diethylaminohexylthio -1 1 ,B-hydroxyandrostan- 17 -onehydrochloride;

3 8- 2-morpholinylethylthio -6u-methyl- 1 1,8-hydroxyandrostan-17-onehydrochloride;

3 ti- 5-morpholinylpentylthio -6u-methyl-1 I/S-hydroxyandrostan-17-onehydrochloride;

3,8- B-dimethylaminopropylthio)-6u-methyl-1 1 3,175-

dihydroxyandrostane hydrochloride;

3,6-(3-dimethylaminopropylthio)-6u,17ot-d]imethyl-11 8,

17B-dihydroxyandrostane hydrochloride;

3 ,8- 3-dimethylaminopropylthio) -6a-methyl-17u-ethynyl- 1 16,17,8-dihydroxyandrostane hydrochloride;

3B-(4-dimethylaminobutyloxy)-6a-rnethyl-11B,17B-dihydroxyandrostanehydrochloride, 17a-acetate;

3,8- (4-dimethylaminobutyloxy)-6a-methyl-l 1B, 17B-di hydroxyandrostanehydrochloride, 17a-phenylacetate;

3,8-(4-dimethylaminobutyloxy)-6a-methyl-11fi3,17fidihydroxyandrostanehydrochloride, 17a-(3-cyclopentylpropionate) and the like.

EXAMPLE 23 3,8-diethylaminoeth0xy-5-andr0sten-l1,17-di0ne A solution wasprepared containing 5 milliliters of glacial acetic acid, 200 milligramsof chromic anhydride and /2 milliliter of water. Into this solution atroom temperature (22 to 24 degrees Centigrade) was introduced 300milligrams of 3B-(2-diethylaminoethoxy)-11,8,17B-dihydroxy-S-androstene. The mixture was allowed to stand at roomtempearture for a period of four hours and was thereupon poured into 50milliliters of ice-water. The ice-water solution was neutralized by theaddition of 10 percent sodium bicarbonate solution. The mixture wasthereupon extracted with three 25-milliliter portions of chloroform, thechloroform extracts were combined, repeatedly washed with water untilneutral, dried over anhydrous sodium sulfate and evaporated. Thethus-obtained residue was recrystallized three times from methanol togive 35-(Z-diethylaminoethoxy)-5-androsten 11,17-dione.

EXAMPLE 24 3 B- (2-diethylaminoethovcy 7ot-methyl-5-androstena 11 -oneIn the same manner given in Example 23, Sfi-(Z-diethylaminoethoxy)17a-methy1-11/3,17,8-dihydroxy-5-androsten was oxidized with chromicanhydride in acetic acid to give35-(Z-diethylaminoethoxy)-17u-methyl-17,8-hy droxy-S-androsten-l l-one.

EXAMPLE 25 3B- (Z-dimethyIaminoethoxy 7B-hydr0xy-5-androsten- J 1 -0m217-acetate In the same manner given in Example 23,3fi-(2-dimethylaminoethoxy)-l1[3,17B dihydroxy 5 androsten 17-acetatewas oxidized with chromic acid to give 35- (Z-dimethylaminoethoxy) 17Bhydroxy-5-androsten-1l one 17-acetate.

In the same manner given in Example 23, other 3- amino-llB-hydroxysteroid ethers can be oxidized to give the corresponding ll-keto ethersof the 3-amino steroids. Representative compounds such produced include:

3 ,8- 4-diethylaminobutyloxy) -5-androsten-1 1,17-dione;

3 B-(6-diethylaminohexyloxy)-5-androsten-11,17-dione;

3 5-( 2-diethylaminoethoxy) -6-methyl-5-androsten-1 1,17-

dione;

3 fi- 3-diethylarninopropoxy -6-methyl-5-androsten- 11,17-dione;

EXAMPLE 27 3,8- (Z-diethylaminoethoxy 7a-methyl-5-andr0sten 1 7 fl-olsulfate A solution of 0.5 gram of 3/3-(Z-diethylaminoethoxy)-17a-methy1-S-androsten-175-01 (Example 2) in 10 milliliters of acetonewas titrated with a 10 percent sulfuric acid solution in water.Titration was stopped at a pH of about 6.5 and the solution wasevaporated. The product was washed with ether and Skellysolve B hexane,the washing discarded and the material twice recrystallized from alcoholto give SB-(Z-diethylaminoethoxy)-17ormethyl-S-androsten-1718-01sulfate.

In the same manner, other mineral acid salts can be prepared from the3-arnino ethers and 3-aminothio ethers in the free-base state byreacting the selected amino steroid with the stoichiometric quantity ofa mineral acid, e.g., hydrobromic, nitric, phosphoric or the like.

We claim:

1. A compound selected from the group consisting of (1) those having theformulae is selected from the group consisting of W is selected from thegroup consisting of and 0:3)

X is selected from the group consisting of fit 01-: uzon wherein n has avalue of 2 to 6, inclusive;

is selected from the group consisting of H30 H C2 OI-I CH N, N and O 1-10 CHgp-Cfig W is selected from the group consisting of t, and O=C|1 l IY is selected from the group consisting of hydrogen and methyl, and (2)a mineral acid salt thereof.

3. 35 (Z-diethylamindethoxy)-17a-ethyl-5-androstenl7B-ol-hydrochloride.

4. 3B (Z-diethylarninoethylthio)-5-androsten-l7-one hydrochloride.

5. 3e (Z-diethylarninoethoxy)-6-methyl-l7a-ethynyl- 5 -androsten-l7[3-01 hydrochloride.

6. 35 (4 diethylaminobutoxy)-l7x-ethyl-5-andro sten-l7 8-olhydrochloride.

7. In a process for the production of steroid compounds selected fromthe group consisting of compounds of Formula I:

wherein V is selected from the group consisting of the elements oxygenand sulfur; wherein W is selected from the group consisting of when V isoxygen; and wherein W is selected from I0 and when V is sulfur; whereinX is selected from the group consisting of HO AcO\ HO O\ CH; 1 \JJ: (E;(J and A: i I l O O H H H30 HG C 5 when W is 1 CH3 110 o=r|3 and 0 andwhen V is oxygen; and when W is a Y (II) wherein R is an alkylene groupwith up to eight carbon atoms and wherein the carbon atoms attached tothe oxy- C and 0 gen bonds are separated by not more than one methylenegroup and V and Y have the same significance as in the Formula I,consecutively (1) with an alkali metal metathetically acting agent and(2) with an alkyl chloride and when Vls Sulfur; and selected from thegroup consisting of compounds of the wherein X is selected from thegroups consisting of formula:

HO AcO HO HO J \& I and t N- o1'12 no1 H" i H" I H 0" I H050" I R ndwhen W is a R o III(OH2),.C1

wherem the parameters and when V is oxygen; wherein Y is selected fromthe group consisting of methyl and hydrogen; and R wherein Ac is theacyl radical of a hydrocarbon carboxylic acid containing from one toeight carbon and n are defined as above. atoms, inclusive;

and, the N-oXides and the mineral acid salts thereof selected from thegroup of mineral acids consiting of LEWIS GO'ITS, Primary Examiner hdrochloric, h drobromic, sulfuric, nitric and phosphoric acid, the stepswhich comprise: treating a compound of LESLIE GASTON MORRIS LIEBMAN thestructure II No references cited.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) THOSE HAVING THEFORMULAE